Parathyroid hormone (PTH 1-34) is the only approved anabolic agent for the treatment of osteoporosis. Its mechanism of action is complex and not fully understood. PTH signals through the PTH1 receptor (PTH1R), as does PTHrp, another natural ligand for PTH1R. We have preliminary data that one downstream effect of PTH1R activation is a reduction in bone marrow adipose tissue (BMAT), due either to a shift in lineage allocation of stem cells and/or lipolysis of existing adipocytes. We are now proposing a mechanistic ancillary study to an ongoing phase III clinical trial of a PTHrp analog, abaloparatide (BA058) to test our hypothesis that changes in marrow adipocytes are tied to the anabolic actions of PTH1R activation. The current randomized placebo controlled trial includes a PTH 1-34 comparator arm, and a sequential alendronate treatment arm followed by a two-year observation phase ( In our proposed ancillary study we will determine if BMAT is altered by activation of the NCT:01657162) for fracture efficacy. PTH1R, measureable on bone biopsies at 18 months by semi-quantitative indices, and test whether the earliest marker of marrow adipocytes , Pref-1, is altered in serum by treatment with PTH-1-34, abaloparatide, or alendronate. We will also examine for the first time if there is a spatial redistribution of adipocytes within the bone marrow that is associated with bone formation and aBMD. To test those hypotheses we propose two aims: Specific aim 1: To determine the impact of PTH 1-34 and abaloparatide on the volume of BMAT (AV/MV) and the number of adipocytes (ANo/MV) per marrow volume. We will assess this by comparing BMAT in 98iliac crest biopsies at 18 months in the BA058 randomized trial between placebo vs combined PTH 1-34 and abaloparatide-treated participants. We will test if aBMD changes from baseline to 18 and 60 months will be inversely correlated with the 18 month AV/MV and ANo/MV on biopsy. We will also explore if there is an inverse relationship between bone formation and ANo/MV and whether the spatial location of marrow adipocytes changes with anabolic therapy as well as their proximity to local bone forming surfaces and how this may impact final aBMD at 60 months. Specific aim 2: To determine if changes in Pref-1 predict BMAT differences in subjects treated with placebo, PTH 1-34, abaloparatide or alendronate. We will measure change in serum Pref-1 between 0 and 18 months and correlate those values with ANo/MV and AV/MV as well as aBMD and P1NP. We also plan an exploratory aim to determine if changes in Pref-1 between baseline and 36 and 60 months predict final aBMD and P1NP, a marker of bone formation. These proposed ground-breaking studies will provide a mechanistic framework for future work to define the cellular basis of anabolic therapies for osteoporosis.